Hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy: The emerging role of non-viral risk factors

Hepatocellular carcinoma (HCC), one of the major malignant lethal tumours, is most prevalent in Asian patients with chronic hepatitis B virus (HBV) infection. Both viral and non-viral factors contribute to the development of HCC. It is established that viral factors associated with HBV DNA level, HBV genotype, designated gene mutation, HBV DNA integration, HBx protein, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and HBV RNA are correlated with hepatocarcinogenesis. Before the introduction of antiviral therapy, viral factors once attracted more attention during the development of HCC. With the widespread use of antiviral therapy, predominantly nucleos(t)ide analogues (NAs), most patients with chronic hepatitis B (CHB) have achieved sustained viral control. The role of non-viral factors, especially modifiable factors, is anticipated to be reinforced in the future. Herein, we reviewed the modifiable non-viral risk factors of HBV-related HCC, in the hope of providing substantial evidence for further development of novel precautionary measures for HCC. In addition, the therapeutic interventions for reducing the risk of HCC, like potential conventional pharmaceutical interventions and lifestyle modification are also discussed in this review. Future studies that would explore the specific mechanism of HBV-related HCC development in patients with satisfactory viral control and related precision treatment are warranted.